Autism risk associated with parental age and with increasing difference in age between the parents.

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985-2004 and followed up to the end of 2004-2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40-49 years vs 20-29 years, RR=1.15 (95% confidence interval (CI): 1.06-1.24), P-value<0.001; fathers⩾50 years vs 20-29 years, RR=1.66 (95% CI: 1.49-1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20-29 years, RR=1.18 (95% CI: 1.08-1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.

The Autism Birth Cohort: a paradigm for gene-environment-timing research.

The reported prevalence of autism spectrum disorders (ASDs) has increased by 5- to 10-fold over the past 20 years. Whether ASDs are truly more frequent is controversial; nonetheless, the burden is profound in human and economic terms. Although autism is among the most heritable of mental disorders, its pathogenesis remains obscure. Environmental factors are proposed; however, none is implicated. Furthermore, there are no biomarkers to screen for ASD or risk of ASD. The Autism Birth Cohort (ABC) was initiated to analyze gene x environment x timing interactions and enable early diagnosis. It uses a large, unselected birth cohort in which cases are prospectively ascertained through population screening. Samples collected serially through pregnancy and childhood include parental blood, maternal urine, cord blood, milk teeth and rectal swabs. More than 107,000 children are continuously screened through questionnaires, referral, and a national registry. Cases are compared with a control group from the same cohort in a 'nested case-control' design. Early screening and diagnostic assessments and re-assessments are designed to provide a rich view of longitudinal trajectory. Genetic, proteomic, immunologic, metagenomic and microbiological tools will be used to exploit unique biological samples. The ABC is a paradigm for analyzing the role of genetic and environmental factors in complex disorders.

Injectable porous nano-hydroxyapatite/chitosan/tripolyphosphate scaffolds with improved compressive strength for bone regeneration.

In this study we have fabricated porous injectable spherical scaffolds using chitosan biopolymer, sodium tripolyphosphate (TPP) and nano-hydroxyapatite (nHA). TPP was primarily used as an ionic crosslinker to crosslink nHA/chitosan droplets. We hypothesized that incorporating nHA into chitosan could support osteoconduction by emulating the mineralized cortical bone structure, and improve the Ultimate Compressive Strength (UCS) of the scaffolds. We prepared chitosan solutions with 0.5%, 1% and 2% (w/v) nHA concentration and used simple coacervation and lyophilization techniques to obtain spherical scaffolds. Lyophilized spherical scaffolds had a mean diameter of 1.33mm (n=25). Further, portion from each group lyophilized scaffolds were soaked and dried to obtain Lyophilized Soaked and Dried (LSD) scaffolds. LSD scaffolds had a mean diameter of 0.93mm (n=25) which is promising property for the injectability. Scanning Electron Microscopy images showed porous surface morphology and interconnected pore structures inside the scaffolds. Lyophilized and LSD scaffolds had surface pores <10 and 2µm, respectively. 2% nHA/chitosan LSD scaffolds exhibited UCS of 8.59MPa compared to UCS of 2% nHA/chitosan lyophilized scaffolds at 3.93MPa. Standardize UCS values were 79.98MPa and 357MPa for 2% nHA/chitosan lyophilized and LSD particles respectively. One-way ANOVA results showed a significant increase (p<0.001) in UCS of 1% and 2% nHA/chitosan lyophilized scaffolds compared to 0% and 0.5% nHA/chitosan lyophilized scaffolds. Moreover, 2% nHA LSD scaffolds had significantly increased (p<0.005) their mean UCS by 120% compared to 2% nHA lyophilized scaffolds. In a drawback, all scaffolds have lost their mechanical properties by 95% on the 2nd day when fully immersed in phosphate buffered saline. Additionally live and dead cell assay showed no cytotoxicity and excellent osteoblast attachment to both lyophilized and LSD scaffolds at the end of 14th day of in vitro studies. 2% nHA/chitosan scaffolds showed higher osteoblast attachment than 0% nHA/chitosan scaffolds.

ViPAR: a software platform for the Virtual Pooling and Analysis of Research Data.

BACKGROUND: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations. METHODS: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates 'virtual pooling' where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage. RESULTS: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory. CONCLUSIONS: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/].

Parental consanguinity is associated with a seven-fold increased risk of progressive encephalopathy: a cohort study from Oslo, Norway.

BACKGROUND/OBJECTIVE: Progressive encephalopathy (PE) is a heterogeneous group of individually rare diseases, many with an autosomal recessive mode of inheritance. We estimated the increased risk of PE associated with consanguinity. PATIENTS AND METHODS: Using a historic cohort study design, the exposures were country of origin (Pakistan versus Norway) and consanguinity. We included children living in Oslo, born between 1985 and 2003. PE cases were retrieved from an electronic registry of diagnoses coded according to the International Classification of Diseases. Incidence rates were calculated for country of origin. We also estimated population attributable risks caused by consanguinity. RESULTS: We identified 30 cases per 79 704 person years with Pakistani origin and 35 cases per 658 932 person years with Norwegian origin. This gave incidence rates of 37.6 and 5.3 per 100 000 person years, whereas the incidence rate ratio was 7.1 (95% CI: 4.2-11.9). The incidence rates of consanguineous versus non-consanguineous of Pakistani origin were 59.6 and 18.7 per 100 000 person years. The incidence rate ratio was 3.2 (95% CI: 1.4-7.2), whereas the incidence rate ratio of non-consanguineous Pakistani versus non-consanguineous Norwegian origin was 3.5 (95% CI: 1.6-7.6). The incidence rate ratio between consanguineous Pakistanis and Norwegians was 11.2. The population attributable risk due to parental consanguinity was 50.3% in the Pakistani sub-population. CONCLUSIONS: We found a seven-fold increased risk of PE in the general Pakistani population, and an eleven-fold increased risk in consanguineous Pakistanis. Pakistani origin by itself was also an independent risk factor. Avoidance of consanguinity in the Pakistani population would result in at least 50% reduction of PE in that group.

[DiGeorge syndrome. An underdiagnosed disease category with different clinical features]. / DiGeorges syndrom--underdiagnostisert sykdomsgruppe med mange fremtredelsesformer.

BACKGROUND: DiGeorge syndrome is estimated to affect one in every 3,000-4,000 live-born individuals. The syndrome is also known as velocardiofacial syndrome (VCFS) and conotruncal anomaly face syndrome (CTFS). The most common clinical features are mental retardation, congenital heart anomalies, primary hypoparathyroidism (with hypocalcaemia), aplasia or hypoplasia of the thymus, and a dysmorphic face. 90% of the affected individuals have a deletion at the long arm of chromosome 22. 80-90% of those deletions are de novo mutations. MATERIAL AND METHODS: This article presents the case of a 32-year-old woman who was diagnosed with DiGeorge syndrome after a grand mal seizure due to hypocalcaemia. The hypocalcaemia was caused by primary hypoparathyroidism. We also give a brief review of the current state of knowledge about DiGeorge syndrome. RESULTS AND INTERPRETATION: DiGeorge syndrome is probably underdiagnosed. A correct and early diagnosis is important in order to prevent medical complications, e.g. hypocalcaemia and hypothyrosis, and to evaluate the patient's overall need of care.